Project 1 Project Summary Therapeutic advances over the past 3 decades now allow most hematologic malignancy patients to achieve major clinical responses. Although the responses can clearly decrease side effects and improve quality of life, most patients still eventually relapse and die of their disease. Our work suggest that the cancer stem cell (CSC) concept may explain why dramatic responses often fail to translate into cures. We found that relapse in many cancers appears to result from rare cells with stem cell characteristics; these so-called CSCs are often biologically distinct from their progeny that form the bulk of the tumor, notably exhibiting substantially different sensitivity to drugs. The rapid responses induced by chemotherapies in most hematologic malignancies are likely a consequence of their impressive activity toward the bulk of the tumor, against which the treatments were developed. The limited durability of many of these responses is consistent with our data showing that the CSCs are often relatively resistant to such therapies. Unfortunately, despite the explosion of work in the area of CSCs, there continues to be few clinical trials studying the therapeutic targeting of these cells and even fewer clinical trials offering proof of the CSC concept that targeting these cells will actually improve outcomes. Our studies have also shown that mismatched allogeneic blood or marrow transplantation (BMT) employing post- transplantation cyclophosphamide (PTCy) is now safe and effective, allowing nearly all patients in need of BMT to undergo this procedure. With issues of donor availability, GVHD, and non-relapse mortality (NRM) now taking on lesser importance in alloBMT, relapse has become by far the major concern. Emerging data suggest that a new, non-tolerant, and non-exhausted transplanted immune system has the ability to augment the activity of many anticancer agents, small molecule as well as immunologic. The MRD state post-alloBMT provides additional advantages for antitumor approaches, in that they will be utilized at lowest tumor burden as well as least tumor heterogeneity including being enriched for CSCs. Accordingly, the overall hypothesis of this Project is that targeting MRD in patients at high-risk for relapse after BMT with CSC-directed therapy, will improve disease control. The overall objective is to explore approaches that target leukemia and multiple myeloma (MM) CSCs and translate promising treatments into clinic in the setting of MRD after alloBMT. Since targets being studied are expressed primarily by AML (CD123) and myeloma (CD19) CSCs rather than the respective bulk tumor, if successful, these data should also provide strong evidence in support of the CSC concept.